Modern approaches to developing new drugs against neglected tropical diseases

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Modern approaches to developing new drugs against neglected tropical diseases

Abstract

The NTDs represent the most common diseases found in the world’s poorest populations, with the majority of the poorest billon suffering from at least one (4). The most frequently found being helminth and selected protozoan infections with other NTDs believed to be extremely common, however there are insufficient data estimates to accurately cite this (5).

There are three main classes of agent typically used to treat NTDs; small molecules, biologicals and vaccines. Small molecules being a low molecular weight organic compound that regulate biological processes (constitute most drugs), biologicals being treatments created using a biological process as opposed to being chemically synthesized (e.g. Herceptin) and vaccines (which can be biologicals).

Introduction

The World Health Organisation (WHO) characterises seventeen different diseases as being “neglected tropical diseases” (NTDs) (1). This characterisation stems from the socio-economic background of those in the areas of highest concentration, the propensity for such diseases being to be found almost exclusively amongst impoverished populations in the developing world (2). The geographic dimension in this placing most individuals in the world’s poorest billion as coming from 58 low-middle income countries in Africa, Asia, the Caribbean and Latin America. With areas such as these lacking significantly in political influence and being perhaps of little concern to the developed world, it is no surprise that such diseases have been given both a low profile and status in terms of public health priorities (1). These diseases impact over 1 billion individuals, are frequently clustered together geographically with individuals frequently suffering with more than one form of infection. The difficulties in treating these individuals stems from the lack of an infrastructure, both social and economic, with enough stability to reliably provide the drugs required in an effective manner, despite the fact that many NTDs can be prevented or treated simply through an improved access to existing treatments, many of which are simply interventions that can be administered by non-specialists (1).

In 2000 the United Nations drafted a set of eight Millennium Development Goals (MDGs) for the sustainable reduction of poverty. Specifically included in this was one aimed at the treatment of infectious diseases in low income countries (MDG 6) “‘to combat acquired immunodeficiency syndrome (AIDS), malaria, and other diseases” (3). This launched several international initiatives for human immunodeficiency virus (HIV)/AIDS and malaria including large scale employment of available drugs and diagnostics.

NTDs generally present various features that single them out compared to other better known infectious diseases. A key feature being that they often lead to chronic morbidities without causing death, this low mortality rate being considered a reason for their longstanding underplayed importance, despite the fact that when factoring in the number of life years lost due to premature disability NTDs are possibly as significant as AIDS or malaria as a public health threat (6). Another aspect of NTDs is that individuals are often infected for decades, possibly their entire lives. With the impact this causes to their health and as such their ability to work, it is vital to understand the significance of these diseases in less developed countries (LDCs) due to the importance of agricultural workers. The reduced efficacy of individuals who work in agriculture due to NTDs has demonstrable economic impact (7).

Research and development (R&D) into vaccines to combat many of the NTDs have lagged behind those targeting AIDS and malaria.

Issues

Scope of problem

Asides from the aforementioned lack of a decent profile or status in public health terms, there are various other issues impacting the production of treatments for NTD’s. With such diseases primarily being apparent in low-middle income countries the financial incentive for large pharmaceutical companies to develop new products perhaps explaining the shortfall in substantive research and development programs for the NTD’s.

In addition to this the much greater visibility of and focus on AIDS as well as malaria have led to the majority of funding and research thus far to go into treating these two afflictions. Whilst they are indeed a major issue, such focus means that research and development for less well known big hitters (e.g. leishmani, trypanosomes, melioidosis and helminthic diseases) lags severely behind.

In addition to the technical issues concerned with creating new treatments, the viability of implementing such treatments in the environments in which NTDs are most commonly found needs to be a key consideration during development. Even if a product is successful it can take a considerable amount of time before a high level of coverage is achieved (e.g. Haemophilus infleunzae type B vaccine – low coverage despite being licensed for almost 20 years) (8). Perhaps the most significant issue is cost. Frequently treatments require sophisticated technology to produce, not to mention the amount of time and money that the research and development stages themselves cost. As aforementioned, this cost is why ascertaining funding for the development of vaccines for diseases that have the majority of their impact in poorer countries is quite difficult, with most NTDs not having a significant US or European market. With large pharmaceutical companies and other funding bodies generally choosing to focus on those treatments which will bring the highest profit, as opposed to the most significant impact on global health. As a result funding is dependent upon charitable donations or the support of governmental organisations. With the available money being tight, often it will be employed into providing what solutions are already available in areas that need it, as opposed to developing new treatments, which carries both a higher cost and risk when considering impact on health (9). Most NTD treatments are being developed through non-profit organisations/product development partnerships (PDPs) such as the Sabin Vaccine Institute or the IVI in Seoul. These aim to produce the vaccines at the lowest cost and the ability to be readily introduced and integrated into LED countries, frequently partnering with manufacturers and clinical trial sites found in some of the more innovative developing countries (e.g. Brazil). The best option then for introduction is the use of pre-existing health systems for their introduction, however this typically is only effective in the more prosperous of the countries involved as it often requires some form of government system e.g. schools for the distribution and where possible government funding in production as most individuals will not be able to afford the treatments themselves (10). In addition to this the free availability of intellectual property used in the treatments greatly reduces manufacturing costs and allows for production to be carried out wherever the infrastructure can support it.

On top of the issue of cost there are various social and ethical issues that need consideration. Primarily in terms of social aspects this refers to native populations approaches to the treatments when offered. There can be issues both in getting an individual to return for repeat treatment – given the large distances often found particularly in sub-Saharan Africa between individuals and the nearest place treatment is available. On top of this there is often difficulty establishing that a full course of a treatment (for example antibiotics) needs to be taken, even if the individual starts to feel better in order for the treatment to be fully effective. Both of these would point towards a single treatment approach being preferable when providing treatments in these areas.

The other social issue is based upon the mistrust of western society that can be prevalent among rural communities particularly in the Middle East. Commonly the way PDPs circumvent this is to use countries such as Egypt, which have advanced scientific communities and resources but are not associated with western society, for development.

One of the most well publicised examples of social issues impacting treatment revolving around AIDS, particularly in sub-Saharan Africa and Latin America. The stigma attached to the disease leading to the ostracism of individuals, be it a result of insufficient education on the matter, superstition, or wider social views, in the case of AIDS the disease is often linked to homosexuality. Communities in LED countries will often shun those who suffer from certain diseases and this can make treatment difficult as it is often crucial to work within established structures to provide treatment. As such educational programs can often help when it comes to distribution of treatment for diseases that have been stigmatised in this way.

Modern approaches:

All NTD drugs must be low cost, not dependant on a cold chain and be easily distributable using the pre-existing infrastructure in affected countries (aforementioned preference for single dose) (17).

Recent studies by agencies including the WHO’s Special Programme for Tropical Disease Research (TDR) show critical gaps in the R&D area for several RTDs (12). A large proportion of the drugs developed to combat NTDs stem from 20th century colonialism and the necessity it provided for the western world to provide treatments for tropical diseases. However as previously discussed the lack of commercial incentives when coupled with increasing regulation has led to the withdrawal of pharmaceutical companies from developing in this area. Hence the importance of bodies like the TDR, which was, and is, involved in product development (13).

Targeting

The use of target identification, through target selection, validation and high throughput screening (14) is a promising concept which unfortunately thus far, despite increased attention recently, has produced minimal results, largely due to high attrition (15). The method is aimed at identifying “hits” with defined modes of action for more study. However recent studies have largely shown poor correlation between inhibition of enzymes and whole cell activity (16). There is limited availability of genetic validation tools and chemical validation is not being widely used. The establishment of the TDR Drug Target Prioritization Networks open source database provides the basic structure to afford the development of various screening options for NTDs

The overall state of development for NTDs as it currently stands is that there has been a lot of basic research into the organisms causing several of the diseases (particularly the helminths), and as such potential targets, however a lack of follow through meaning there has been little drug discovery and development until very recently. Recent advances in automated microscopy have begun to impact drug discovery by replacing other microscopic observation methods (18), the use of phenotypic screens has meant that there has been a reliance upon low/medium-throughput whole organism assays, which prevented access to a critical mass of compounds for further investigation. The new methods have the ability to increase throughput with the production of high-content screens (HCSs) (18). Definition of the target of an active compound is not strictly speaking always required in NTD drug discovery, however the process must be in line with a target product profile (TPP) for each disease, leading to a more streamlined discovery process providing a non-wasteful end product.

An example of target-based drug discovery for human African trypanosomiasis (HAT)

HAT is endemic in sub-Saharan Africa, it is caused by the parasites Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, consists of two stages (peripheral infection/enters central nervous system (CNS)). It is fatal when not treated and currently has treatments for both stages although these are ineffective due to toxicity and/or poor efficacy (20) in addition to which the treatments are not appropriate for the area.

There have been few programmes developing new drugs for HAT, however recently this has changed as with other NTDs and the infrastructure required for drug discovery has been put into place. The aforementioned TPPs will inform drug discovery from the beginning and helps in defining the molecular target and chemical matter developed. The TPP for HAT requires the molecular target to; “be essential for parasite viability, have a rapid inhibited cidal effect and be amenable to inhibition by small drug-like molecules having the correct physiochemical properties to be orally bioavailable and cross the blood-brain barrier.”(19). Current methods for target based drug discovery generally involve the screening of diverse/focussed libraries against the target. Any hits produced are characterised before being put through design, synthesis and testing against both proteins and the cell. The compounds have to be shown to be acting on the target to cause inhibition leading to death of the parasite before the use of animal infection model assays to ascertain if the drug is reasonably viable. As is evident it takes a lot of input, both in terms of time and resources before any idea on the validity of the chosen target, meaning that careful selection from the start can greatly benefit discovery later on in the process (19).

.Target identification

  • High throughput methods, e.g. microarrays, high throughput sequencing, protein microarrays, chemical genetics (Shokat, 2002), reverse genetics (Hung, 2006).
  • Fragment based drug design
    • See, for example, Astex Pharmaceuticals; Shoichet, 2004
  • Virtual screening
    • Read Schneider, 2002; Rees, 2004
  • Improved vaccine strategies
    • DNA vaccines
    • Conjugate vaccines (e.g. S. pneumoniae; Meningitis Vaccine Project)
    • Subunit vaccines
    • Synthetic biology
  • Correlates of protection
    • Can’t do efficacy studies for many diseases (i.e. those without a cure), so you need some indicator (e.g. antibody titre) that is a “correlate” of protection.
  • Some interesting ideas
    • For conjugates – use bacterial glycosylation pathways to prepare in one organism (see Brendan Wren’s work on pglB)
    • Nanotechnology for better delivery.

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